DE2147095A1 - Clear, liquid, laxative, antacid - Google Patents

Description

2U7095

PAIlNrANWXlJF

PROF. DR. DR. J. R E ITSTÖTT t "R

D R. -1 N G. WOLFRAM D Ü N T Li

DR. KARL GEORG LÖSCH

O HOi) (I Ml) NCHLN l.i IIAIJi IlMÜU !. .1. . '.:. r I KNIfUI '(OHIIi .1 / IiH' 'I

Munich, ^ M / 11709

BRISTOL MYERS COMPANY 345, Park Avenue, New York, N.Y. UNITED STATES.

Clear, liquid, laxative, antacid

The present invention relates to a clear liquid, laxative, or laxative antacid, the magnesium hydroxide, contains an amino acid and an oxy or oxo acid in an aqueous medium.

The present invention thus relates to clear, liquid laxative antacid agents. It particularly affects liquids Products that serve both as laxatives and as antacids and that are also characterized by it are that they present visually attractive dosage forms that are more palatable than similar products are currently on the market.

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Aqueous antacids or laxatives containing magnesium compounds are known from the prior art. For example, an aqueous magnesium hydroxide preparation is used useful as an antacid or laxative, for several years as "Milk of Magnesia" sold. This product is a white, opaque, more or less viscous suspension of magnesium hydroxide in water. It contains varying amounts of water and the

it is noteworthy that when standing it separates into two phases. This product has the obvious disadvantage that it must be shaken thoroughly before administration. In addition, it has a chalky nuisance A taste that is difficult to mask.

Another magnesium-containing product that is widely used pharmaceutically is magnesium citrate, which is sold as a clear solution containing magnesium citrate in concentrations of 1.55 to 1.9 % as MgO. This remedy is recommended for its laxative properties, but it does not have acid-binding properties. In addition, it has a distinct, unpleasant salty taste and must be consumed in large quantities to be effective. The suggested dose for this product is 6 to 12 fluid ounces (0.177 to 0.355 liters).

According to the invention it has now been found that crystal clear, liquid laxative, acid-binding products can be produced which contain high concentrations of magnesium in the form of the oxide (for example 7.4 %) and can easily be made palatable. These products are at least four times as effective as laxatives as milk of magnesia, which has roughly the same magnesium content. In addition, they have acid-binding properties that are roughly the same as those of milk of magnesia and are far superior to those of magnesium citrate, which, as stated above, has no acid-binding effect.

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Accordingly, it is an object of the present invention to provide effective liquid, laxative, acid-binding products, which are clear so that they are convenient dosage forms which can be made more palatable than that products known from the prior art.

Another object of the present invention is to provide magnesium-containing products having the properties described above that avoid the disadvantages of similar commercially available laxative and / or antacid products.

According to the invention, crystal clear aqueous solutions which have laxative and antacid properties are obtained by ingestion of magnesium hydroxide, a non-toxic pharmaceutical compatible organic oxy or oxo acid and a non-toxic pharmaceutically acceptable amino acid in one aqueous medium produced. A mixture of magnesium hydroxide, the amino acid, is used in the manufacture of this remedy and the oxy or oxo acid in water is preferably heated to boiling and then filtered to produce a clear solution. The magnesium hydroxide can be supplied as such or in situ are formed. However, the former procedure is preferably used.

Any of a variety of pharmaceutically acceptable ones Amino acids can be used in the present invention. Usually it is a-amino acids that are non-toxic and pharmaceutical are compatible. One class of amino acids that are particularly useful are those that occur naturally or are derived from Hydrolysis of proteins can be produced. These include amino acids such as: lysine, tryptophan, histidine, phenylalanine, Leucine, isoleucine, threonine, methionine, valine, arginine,

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Glycine, alanine, serine, norleucine, glutamic acid, proline, hydroxyproline, tyrosine,> cystine, aspartic acid, citrulline, etc.

The amount of amino acid that is taken up in the agents according to the invention varies somewhat and depends on the magnesium hydroxide content together. Usually the molar ratio I of magnesium hydroxide to amino acid is in the range ' from 1 mole of magnesium hydroxide to about 0.5 to 5 moles

Amino acid and preferably in a ratio of 1: 2. ·

Be spent acids, in addition to the amino acid according to the invention comparable], are oxo or oxycarboxylic acids, ie: eine'Keto- or a hydroxy acid. The selected acids of this group are also non-toxic, pharmaceutically acceptable and [I serve an at least two-fold purpose. They are used to j to adjust the pH of the agent to an orally acceptable level; reduce and to further stabilize the solution in order to prevent the precipitation of insoluble magnesium compounds during storage. The oxo or oxy acid is also preferably selected for taste as the product is intended for oral administration. Accordingly, [the chosen acid is usually per se organoleptically tolerated! For example fruit acids. However, if the acid used! ! has an unpleasant taste, this can be compensated for by suitable! flavors. <

Among other things, the oxo or oxy acids are added in order to reduce the pH of the agent formed by mixing magnesium hydroxide and amino acids. Usually> [is sufficient oxo or oxy acid added to lower the pH to an orally acceptable level, that is at least about 9.5 and preferably at least about 8.0. The lower pH limit of the agent can vary widely, depending on the particular amino acid chosen and the oxo or oxy acid. In general, however, the pH will not be less than about 7.0.

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The amount of oxo or oxy acid used depends on the amount and type of amino acid used. In general it is determined by the desired final pH value, i.e. the acid is added in an amount that is sufficient to give the agent the desired pH.

The oxo or oxy acid used can have the formula XRCOOH are described, in which X is the group = 0 or -OH and R is an organic radical. The organic radical R can also contain other keto oxygen atoms and / or hydroxyl groups. In addition, this organic residue can be further j Carboxy groups.

ι,

The oxy or oxo acids which can be used according to the invention can specifically described with the following general formula will

I in what

(Z) _c (Y) _b (X) _a R-COOH

R is an aliphatic carbon chain with up to

to 5 carbon atoms,
X hydroxy,
Y keto oxygen,
Z carboxy,

a is a number from 0 to 5>
b is a number from 0 to 1,
jc is a number from 0 to 2

'■ mean, where the sum of a + b + c is equal to 1 to 5, ■ the radicals X, Y and Z are bonded to the carbon chain R ^: and the remaining valences on the carbon chain R,; those not of hydroxy, keto oxygen or carboxy are ingested, carry hydrogen. As examples of specific, oxo or oxy acids which are useful according to the invention, the following can be mentioned:

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Citric acid (hydroxypolycarboxylic acid), gluconic acid (polyhydroxycarboxylic acid), Lactic acid (monohydroxymonocarboxylic acid), levulinic acid (ketocarboxylic acid).

It has also been found that adding a polyhydric alcohol (Polyol) to the agents according to the invention serves to further stabilize them and the precipitation of insoluble To prevent magnesium compounds, especially at elevated temperatures. If they are expertly selected, know they also serve to give the remedy a pleasant sweetness. These alcohols are non-toxic and pharmaceutical compatible and can generally be described with der.Formel OHROH, where R is an organic radical, which can contain further hydroxyl groups. The polyhydric alcohols useful in the present invention can more accurately by the general formula

[CH ₂ OH (CHOH) _x CH ₂ -O-] [R (CHOH) _x CH ₂ OH] i or anhydrides thereof, wherein

R denotes the monovalent radical CH ₂ OH- or the

divalent radical -CHOH-, χ a number from 0 to 4 and y 0 or 1

where the radical R is -CHOH- when y is 1, and CH _{2 is} OH- when y is 0. So they can be simple carbon-chain-linked polyhydric alcohols, or anhydrides thereof, or ether-linked polyhydric alcohols or their anhydrides. The anhydride form of these polyhydric alcohols is generally found in sugars and other lactones.

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As examples of specific polyhydric alcohols according to the invention One can use glycerin,, sorbitol, sucrose or other non-reducing sugars cite etc.

The amount of polyhydric alcohol, if any, can vary. You can for example ötwa 5 to make up about 40% by weight of the total composition.

Optionally, a preservative can be added to the invention Means are given to combat the growth of microorganisms. Any of a A variety of preservatives can be used for this purpose, such as sodium benzoate, ethyl alcohol, Benzoic acid, ethyl, methyl, butyl, propyl paraben, sorbic acid, sodium sorbate, etc. In a preferred embodiment In the present invention, ethyl alcohol is selected as the preservative. Besides the preservation - Agents can be added to other ingredients to improve the organoleptic or other properties of this agent to improve. These include flavorings, coloring agents, etc.

The unit dosage for administering the agent of the invention will vary somewhat with the particular nature of the agent. Generally one dosage unit consists of about 5 to 15 ml of the liquid preparation. This will be effective Laxative and antacid effect achieved.

The following examples are intended to illustrate the invention in more detail. however, do not limit them. Unless otherwise stated, the amounts of the ingredients are in percent by weight, based on indicated on the total weight of the agent.

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'Example 1 Mg (OH) ₂ Weight % I. Glycine 10 citric acid 20th H ₂ O 14th 100

The components mentioned are heated to the boil and filtered. The resulting solution is clear, has one pH 8.5 and a mild taste. A unit dose of this material consists of 5 to 15 ml of liquid.

Examples IA and IB

It provides a means according to Example 1 but using 30 wt .- ό lactic acid instead of citric acid and 40 wt -.% Water.

Similarly, a composition is prepared according to Example 1 and 35% by weight of levulinic acid is used instead of citric acid and 35% by weight of 96 H ₂ O.

i
Example 2

Mg (OH) ₂ . 7.5 wt. 56

Glycine 14.5 wt. 96

Citric acid 11.5% by weight

Sorbitol (70 # aq.

Solution) 29.5 wt

H ₂ O 37.0 wt. 96

100.0 wt. 96

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The above ingredients are heated to the boil and filtered. A clear solution with a pH of 8.35 is obtained. A dosage unit consists of 5 to 15 ml of the liquid.

! Example 2A

^: A composition according to Example 2 is prepared and used [instead of sorbitol, 30% by weight of glycerol and the composition contains; 37.5% by weight of water.

example

Mg (OH) ₂

Glycine

citric acid

Sorbitol (70 96ige
Solution)

Sucrose
HoO

7.5 wt. 96

14.5 wt. 96

12.0 wt. 96

20.0 wt. 96

15.0 wt. 96

31.0 wt. 96

100.0 wt. 96

The above ingredients are heated to the boil and filtered. A clear solution with a pH of 8.30 is obtained. A unit dosage of this agent consists of 5 to 15 ml of the liquid.

example

Mg (OH) ₂ - 9 - 7.5 Wt% Alanine 2098 14.5 Weight-96 citric acid 11.5 Weight-96 Glycerin 30.0 Weight-96 HoO 36.5 Weight-96 100.0 Weight-96 U / 1 7 0'9

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!
The above ingredients are heated to the boil and. filtered. A clear solution with a pH of 8.35 is obtained.

i ·

i One dosage unit of the agent consists of 5 to 15 ml, the liquid.

Examples 4 A and 4 B

j It provides a means in accordance with Example 4 ago, but using 24.5 wt% of lactic acid instead of citric acid and the water, content macht23,5 96 parts by weight of the agent from.

; A composition according to Example 4 is prepared in a similar manner, but uses 30% by weight of levulinic acid instead of citric acid _ί and the water makes up 18% by weight of the composition.

j Example 4C

! A composition is prepared according to Example 4, but used

Wt .-% sucrose instead of glycerin and the agent 'contains 46.5% by weight of water.

Example 5

Mg (OH) ₂ '7.410 wt. 96

Glycine 14.810 wt. 96

Citric acid 12,600 wt. 96

Sorbitol

(70 96% aq. 18.510 wt. 96

Solution;

Ethyl alcohol (95 96ig) 6.140 wt. 96 sucrose 9.630 wt. 96

Flavor 0.125 wt. 96

^H 2 ° 30.775 wt. 96

100,000 wt. 96

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/ A

The above ingredients, with the exception of the ethyl alcohol and the aroma, are heated to the boil, filtered and cooled. After cooling, add the alcohol and aroma. A clear, tasty solution with a pH of 8.0 is obtained. One The unit dosage of this agent consists of 5 to 15 ml of the liquid.

As mentioned above, the prior art magnesium citrate has no acid binding capacity. The invention However, compositions, although containing an acid that may be citric acid, are essentially the same acid-binding power like milk of magnesia. The products according to the invention, for example according to Example 5 » 23 ml 0.1 η HCl per ml to get a pH of 3> 5, while milk of magnesia requires 26 ml of 0.1 η HCl to maintain the same pH. The agents according to the invention are however, as detailed below, far more effective as a laxative than milk of magnesia.

According to Goodman and Gilman (1965), magnesium-containing compounds are laxatives due to the fact that the Magnesium ion is not absorbed in the gastrointestinal tract, so it remains in a soluble form in the lumen and holds a certain amount of water back to maintain isotonicity. The increased water that was in the lumen is retained, acts as a mechanical stimulus that increases intestinal motor activity and the intestinal contents is quickly brought into the colon. The normal absorption of fluids in the large intestine is similarly hindered, the contents of the large intestine remains fluid and is quickly excreted.

The laxative effects of orally administered according to the invention Agents and a leading, commercially available milk of magnesia are used in rats, using two

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Parameters compared. On the one hand, the amount of moisture in the small intestine is measured and, on the other hand, the amount of moisture moving forward Effect of the small intestine, expressed as a percentage of the stretch of the small intestine traversed by a test meal will. Both procedures are detailed below.

Comparison of the laxative effectiveness between the agent according to the invention and the commercially available one Milk of Magnesia, for the moisture content in the small intestine of rats

Tested materials:

a) 1.0, 2.0 and 4.0 ml / kg doses of a clear liquid agent according to the invention, denoted by Formula 195 and has the following composition:

Formula 195 Weight % 6.67 Magnesium hydroxide powder 13.33 Glycine Citric acid, powder, 10.00 anhydrous Sorbitol (aqueous solution, 26.60 70%) 10.47 Ethyl alcohol, 95% USP 0.20 Aroma 32.73 water

100.00

b) 1.0, 2.0 and 4.0 ml / kg cans of commercially available milk of magnesia. "

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(c) control 4.0 ml / kg tap water,

Procedure: 140 non-fasted rats (20 per test group) will use either Formula 195, commercially available milk of magnesia or control fluid administered. Every animal will Eat 15 minutes after administration and the contents of its small intestine are placed in a small tared aluminum weighing cup pressed. The contents are dried to a constant weight which is recorded. The difference between gives the wet and dry weight of the contents of the small intestine; Amount of moisture found in the small intestine. The bigger the amount of moisture, the more effective the test product is as a laxative.

The test is carried out over 4 days with 35 rats (5 per group) on each of the test days. The test groups are balanced with respect to the weight of the test animals.

The results of these experiments are given below Table I summarized. The abbreviations in this table have the following meanings:

(1) ClA, CL2 and CLl - animals given 4, 2 and 1 ml / kg formula 195 was administered,

(2) PH4, PH2 and PHl - animals which are 4, 2 and 1 ml / kg, respectively commercially available milk of magnesia has been administered,

(3) PL - animals given a placebo (4 ml / kg tap water).

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Table I.

Comparison of a clear, laxative, anta iden By means of Formula 195 and commercially available milk of magnesia

Average
body weight
G 15th CIA •
Average Wet weight avg. Dry weight
the contents of the small intestine
gg , 997 , 396 CL4 CL4 0.601 CL4 158, '00 CL2 , 494 , 941 CL2 CL2 0.552 CL2 156 15th PH4 , 793 , 355 CLl CLl 0.475 PH4 155, 40 PH2 , 780 , 305 PH4 PH4 0.456 PH2 152, 10 PL , 581 , 126 PH2 PH2 0.438 CLl 151 65 CLl , 345 , 908 PL PL 0.437 PL 150 95 PHl , 275 , 846 PHl PHl 0.429 PHl 146, Average Damp
salary
G Average relationship
Moisture content too
Dry weight of the small intestine
content 5,750 CL4 .5,542 CL2 5.451 CLl 4.988 PH4 4.758 PH2 4,362 PL 4,299 PHl 3 3 3 2 2 2 2 2 2 2 2 1 2 1

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From Table I it can be seen that both the clear, laxative, antacid agent according to the invention and the milk of magnesia increased the amount of water in the intestinal lumens of non-fasted rats to which the drugs had been administered orally. The absolute amounts of water were considerably different for each dosage range of clear laxative, antacid, but not for each dosage level of milk of magnesia. The response to 1 or 2 ml / kg of the latter was no different from the response to the control fluid and the response to 4 ml / kg was no different from 1 ml / kg of the clear, laxative, antacid agent of the present invention.

When the water content in the intestine is expressed as a percentage of the dry weight of the intestinal contents, the response to the doses of the clear, laxative, antacid composition is still graded, although not as significant, but the response to milk of magnesia is not. According to this measurement, however, all three doses of the clear, laxative, antacid agent according to the invention exceeded the effectiveness of even the highest dose, 4 ml / kg milk of magnesia. On this basis, the clear, laxative, antacid agent is 12 1/2 times more effective than milk of magnesia, with a lower limit of 4. The estimate of effectiveness is necessarily broad because of the flat course of the dose-effect curve.

Comparison of the laxative effectiveness between ι. agents according to the invention and commercially

■ available magnesia milk regarding the! gastric motility in rats

! Tested materials:

1.0, 2.0 and 4.0 ml / kg clear laxative formula 195 * ^, 0, 2.0 and 4.0 ml / kg of commercially available magnesia milk. *

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j * In a meal consisting of 10 % charcoal suspended in 5 % acacia gum.

A test meal consisting of 10 % charcoal suspended in 5 % acacia gum serves as a control.

iProcedure:

₍ Fasting animals are administered orally 10 ml / kg with a test meal consisting of 10 % charcoal suspended in 5 % acacia gum. The animals in the comparison group only receive the test meal, while those in the test groups receive a test meal that also includes the Contains ιιηΐβΓεμοηεηαβ preparation j. Exactly 15 minutes after administration, the animal is killed and the intestine is removed. The length of the intestine from the pylorus to the cecum and the distance that the test meal takes

1 has passed through in the intestine are measured. The latter! Measurement is also given as the "percentage of length of the bowel passed through". The distance the test meal covered in the intestine and the % intestine covered indicate the degree of the laxative effect. The test is carried out for k days with 35 animals (5 per group) on each test day. The test groups are balanced with regard to the body weight of the animals.

The results of these experiments are summarized in Table II below.

The abbreviations ClA, CL2, CLl, PH4, PH2, PHl and PL have the same meaning as in Table I.

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Table II

Comparison of clear, laxative, antacid, Formula 195 with commercially available milk of magnesia

Average Average ι

Body weight length of the intestine.

g cm * i

^ Denotes the presence

25 PL 121 03 PHl a pronounced

, O VL · ± <LL, Oi fm interaction between

144.15 PH2 119.28 PL administration day and

, _T product. Therefore were

143.15 CL2 118.83 CL2 _{the product} comparisons

Ϊ43.1Ο PHl 118.08 PH2 on one test day

142.90 CIA 117.09 CIA '. ;

142.50 CLl 116.78 PH4

139.85 PH4 115.53 CLl;

Average length of the intestine (cm)

6.1.70 7.1.70 8.1.70 9.1.70

119.28 CLl 126.02 PHl 120.78 PH4 124.80 PL

118.00 PH2 121.52 PH2 120.02 PHl 123.52 PHl

117.78 PH4 121.28 PL 119.76 CL2 122.82 CIA

116.76 ClA 119.26 CL2 118.02 PL 122.78 CL2

114.54 PHl 116.52 CLl 114.52 CL4 118.52 PH2

113.52 CL2 114.78 PH4 114.26 PH2 117.28 CLl

113.02 PL 114.26 CIA 109.04 CLl 113.76 PH4

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Average traversed
Length (cm)

Average %
traversed intestine

98.47 CLl 98.10 CL4

97.58 CL2 89.33 PH4 88.90 PH2 87.96 PHl

81.59 PL

82.0 CIA 81.4 CLl

80.8 CL2

72.9 PH2 72.7 PH4 71.2 PHl 64.9 PL

As stated above, both drugs are taken orally on an empty stomach
Rats in the same dose range of 1, 2 and 4 ml / kg
tested. Although the response to both drugs is about it!

tended to correlate directly with the size of the ί dose given to the rats, it was statistical
within any drug treatment not significantly different from one another, although both drug effects differ from ^; the effect of the comparison placebo differed.
As a result, there is no dose-response relationship on the basis of which one could estimate the relative efficacies. However, based on the minimum and maximum response to these doses, it is clearly evident that the
peristaltic effect of the lowest dose, 1 ml / kg, des
According to the invention, clear, laxative, antacid agent | exceeds that of the highest dose of 4 ml / kg milk of magnesia, · which to a large extent affects the relative efficacies ^! confirms, as they have been determined on the basis of the hydration effect described above.

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Claims (10)

2 H 7095. M / 11709 W claims 1. Clear, liquid, laxative, antacid agent, characterized in that it is an aqueous medium pharmaceutically effective amount of 'magnesium hydroxide, one i non-toxic, pharmaceutically acceptable amino acid and a non-toxic, pharmaceutically acceptable oxy-: or oxo-acid, wherein the agent comprises sufficient magnesium i contains hydroxyd to act as a laxative, antacid act, and contains enough amino acid and oxy or oxo acid to prevent the precipitation of insoluble magnesium compounds ! to prevent in the clear liquid. ^] 2. Means according to claim Ij, characterized in that its pH is no higher than about 9 »5. 3. Composition according to claim 2, characterized in that enough oxo or oxy acid is present to the agent to give a desired pH of no more than about 9.5. 4. Mittel. according to claim 3, characterized in that the agent has a pH no greater than about 8.0. 5. Agent according to claim 4, characterized in that ■ it contains the magnesium hydroxide and the amino acid in a molar ratio of 1 mol of magnesium hydroxide to 0.5 to 5 mol of amino acid. - 19 - 2098U / 1709 2H7095 «Ι Λ M / 11709 6. Means according to claim 5 »characterized in that the amino acid glycine and the oxo or oxy acid citric acid are. 7. Agent according to claim .6, characterized in that the amino acid alanine and the oxo or oxy acid Are citric acid. ■ 8. Agent according to claim 1, characterized in that it is a non-toxic, pharmaceutically acceptable contains polyhydric alcohol. 9. Means according to claim 8, characterized in that the polyhydric alcohol is sorbitol, sucrose, glycerin, or a mixture thereof. 10. Dosage unit of the agent according to claim 1, characterized in that it contains 5 to 15 ml of the agent according to claim 1 contains. - 20 - y "209BTiTTTITB"